Project Summary/Abstract Type-2 diabetes (DM) disproportionately affects Native Hawaiians (NHs) compared with the general U.S. population. Under an obesogenic environment (i.e. high-fat diet, sedentary lifestyle and other behaviors associated with obesity), immune inflammation precedes and contributes to the development and progression of DM. What remain unclear are the molecular mechanisms by which specific immune cells modify their inflammatory potential and associate with insulin sensitivity in DM. Identifying and characterizing epigenetic mechanisms involved in immune inflammation will be of significant importance in understanding the development, progression, and treatment of DM among health disparity populations. We have established collaborations with the NH community and DM researchers to recruit DM participants to characterize epigenetic mechanisms including DNA methylation in regulating monocyte cells inflammatory function in DM. Our preliminary data in NH participants' undergoing a DM intervention revealed participants' ex vivo monocyte inflammation response reduced when glycemic control improved. Moreover, the altered inflammation state of monocytes related to significant differences in DNA methylation and gene expression of proinflammatory genes. Based on our preliminary findings, our hypothesis is that the obesogenic environment leads to DM influences the DNA methylation landscape of monocytes, including at pro-inflammatory genes, which pre- conditions their inflammatory potential. This altered epigenetic state primes monocytes to over-respond to inflammatory stimuli, leading to chronic inflammation and increased insulin insensitivity in the diabetic state. We will test this hypothesis through the following Specific Aims: (1)Determine the relationship between monocyte inflammatory response and insulin sensitivity in diabetic and normal, non-diabetic participants from the NH community. Here we measure monocyte cells functional response to inflammatory stimuli by an ex vivo assay developed by our collaborator. (2)Measure and compare the DNA methylomes of monocytes from diabetic and normal, non-diabetic participants. We will use a methylation array to evaluate and compare genome-wide DNA methylation patterns from diabetic and normal, non-diabetic individuals monocytes at >850,000 CpG sites across the human genome. (3)Characterize and compare the transcriptomes of monocytes from diabetic and normal, non-diabetic participants. We will examine gene expression and pre- mRNA splicing genome-wide using RNA-Sequencing and determine the functional consequences of differential DNA methylation. Collectively, this unique clinical, immunological, and epigenomic database may enable the development of novel molecular diagnostic assays to inform patient-specific health care decisions to reduce DM-associated health outcomes in the NH/PI community.